Esters of amino alcohols



United States Patent g 2,838,521 ESTERS or AMINO ALCOHOLS} Carl 1 Lnnsfoi'd, Richmond, Va., assignor to A. H. Robins Company, Inc., Richmond, Va., .a corporation of Virginia I No Drawing. Application May 17, 1956 i Serial No. 585,403

6 Claims. (Cl. 260326.3)

lilydrocarbon radical Among the hydrocarbon radicals included within the scope of the present invention are alkyl and alkenyl groups which contain at least four carbon atoms, and cycloalkyl, aryl, and aralkyl radicals. The acid-addition salts of such compounds are also included. p

Evaluation of the compounds of the above concept by standard pharmacological tests have indicated the utility thereof as local anesthetics comparing favorably in potency with procaine and Xylocaine.

The prior art picture into which this invention falls is divergent from the structure of the novel compounds of this invention, 22CA1774 (1928) disclosing the benzoate hydrochloride salt of N-methyl-beta-hydroxypyrrolidine which may alternatively be expressed as N-methy1-3- pyrrolidyl benzoate hydrochloride. This compound is stated to have anesthetic properties.

Patent 2,479,971 to Scholz discloses alkyl esters of the pyrrole-3 carboxylic acids and teaches their utility as rubber accelerators and local anesthetics.

Patents 2,605,266 and 2,719,851'to Reid disclose 1- pyrrolidylalkyl aroyl esters where the esterification of the hydroxyalkylpyrrolidyl nucleus occurs in the alkyl side chain, not directly on the pyrrolidine ring. The compounds in both patents are stated to have value as. local anesthetics.

The compounds of the present invention are also related generally to that class of known local anesthetics which are esters of para-aminobenzoic acid and have a specific effect on the sensory nerves or their endings. Among such known compounds is procaine.

It has been the aspiration of the workers in the art to strive for relatively long action as well as high activity coupled with low toxicity. Xylocaine and procaine, while widely used, are not completely satisfactory local anesthetics. Therefore, it is an object of the present inven tion'to provide novel esters of N-substituted-3-pyrrolidinols.

It is a further object of the present invention to prepare novel para-aminobenzoic acid esters of N-hydrocarbonsubs'tituted-3-pyrrolidinols.

It is an additional object of the presentinvention to provide novel'local anesthetic compositions having high activity compared with known compositions.

Qther objects of the invention will become apparent to those skilled in the art to which this invention pertains.

Members of the new group of compounds include esters of B-pyrrolidinols wherein the N- or l-position is substituted by a hydrocarbon radical such as alkyl, cycloalkyl, aryl, aralkyl, alkenyl and the like. In the case of alkyl whereas the N-methyl, N-ethyl and N-propyl show some activity as anesthetic agents, it has been found that a sharp and abrupt increase in activity occurs in the N- or l-substituted compounds where alkyl is C-4 or greater,

Thus, the

as for example, in the N-butyl derivatives. para-aminobenzoic acid esters of 3-pyrrolidinols wherein N is substituted by a lower alkyl radical are preferred, especially those having N-radicals containing at least 4 carbon atoms. It appears that lower alkyl radicals containing 4 to 6 carbon atoms substituted on the pyrrolidinol nitrogen yield compounds having unexpectedly good local anesthetic potency when compared with Xylocaine and procaine.

The preferred N-alkyl species embodiments are the 1-isobutyl-3-(para-aminobenzoyloxy) pyrrolidine and the l-tertiary-butyl 3 (para-aminobenzoyloxy) pyrrolidine members.

Among the other hydrocarbon radicals are the alkenyls,

Additional hydrocarbon radicals include the cycloalkyls 7 containing at least 4 carbon atoms. The cyclohexyl member, the 1-cyclohexyl-3-(para-aminobenzoyloxy) pyrrolidine, is preferred.

Among the hydrocarbon radicals of the aryl and aralkyl series the preferred species embodiments are the phenyl and benzyl, respectively.

The novel compounds of the present invention are prepared by the reaction of the appropriate N-substituted-3- pyrrolidinol with a p-nitrobenzoic acid halide, preferably p-nitrobenzoyl chloride. The nitro group of the resulting N-substituted-3-(para-nitrobenzoyloxy) pyrrolidine is then reduced to an amino group by employing any of the commonly used methods, e. g., glacial acetic acid and zinc dust, or Raney nickel and hydrogen. The finally reduced products are the N-substituted-3-(para-aminobenzoyloxy) pyrrolidines, which may also be regarded as N-substituted-B-pyrrolidyl para-aminobenzoates, and the acid addition salts thereof.

Since many of the starting N-substituted-3-pyrrolidinols are themselves novel compounds, methods for their preparation are given in detail in the preparations. The 1- substituted-3-pyrrolidinol amino alcohol starting materials may be conveniently prepared by a ring formation process using the corresponding dihalomonohydroxy alkane and a primary amine similar to the method disclosed at 76 JACS 3548 (1954), as illustrated in Preparation 1.

Preparation 1.- 1-n-butyl-3-pyrr0lidin0l Into a 3-liter, round-bottom, three-neck flask fitted with i a mechanical stirrer, condenser, dropping funnel and thermometer was introduced 731 grams (approximately 10 moles) of n-butylamine, and it was heated to reflux. The heating source was removed and 1155 grams (approximately 5 moles) of 1,4-dibromo-2-butanol was added dropwise, with stirring, at a rate which maintained refluxing of the amine. When the temperature of the mixture became -140 degrees centigrade it was maintained there by adjusting the rate of addition of the 1,4- dibromo-Z-butanol and for an additional two hours by external heating after addition was complete. Approximately one liter of water was added tothe reaction mixture, and the resulting solution was acidified with concentrated hydrochloric acid, cooled and extracted with ether. The aqueous layer was basified with 50 percent aqueous sodium hydroxide, saturated with potassium carbonate and extracted with chloroform. The chloroform solution was concentrated and the residue was fractionally distilled at reduced, pressure; yield 440 grams (62 percent). of 1-n-butyl-3-pyrrolidinol; B. P. 120-124 degrees centigrade at 22 millimeters.

.Analysis.Calculated for C H NO: C, 67.09; H, 11.96. Found: C, 67.09; H, 12.11.

The 1,4-dibromo-2-butanol used in the preparation of the 1-substituted-3-pyrrolidinols is conveniently prepared according to the following procedure:

1,2,4-butanetriol (2120 grams, moles) was heated in a three-liter, round-bottom, three-neck flask fitted with a gasinlet tube, thermometer and'water separator to 120 degrees. centigrade. A rapid stream of dry hydrogen hydrogen bromide was passed in and the temperature was maintained at 130-140 degrees centigrade for approxi-. mately two hours until approximately 90 percent of the stoiehiometric amount of water had separated. The remaining water wasv removed in vacuo and the residue distilled at reduced pressure; yield 3490 grams (75 percent); boiling range 153-160 degrees centigrade at 45. millimeters (98 degrees centigrade at 3.5 millimeters).

The l-substituted 3-pyrrolidinol starting materials may also. be prepared by reduction of the corresponding ketones with suitable reducing agents, as illustrated in Prep.

arations 2 and 3. The ketones per se are well known in the art, e. g., 73 JACS 2372 (1951) and are generally prepared by the Dieckmann cyclization reaction.

Preparation 2.-l-butyI-S-pyrrolidinol To illustrate this latter process wherein lithium aluminum hydride is employed for reduction, 1-butyl-3-pyrrolidone (16.0 grams, 0.113 mole) was added dropwise with stirring to a suspension of 3.0 grams (0.077 mole) of lithium aluminum hydride in 300 milliliters of dry ether. The mixture, was refluxed and stirred for minutes after all ketone was added; The excess hydride was hydrolyzed with water and the mixture filtered. The ether filtrate was concentrated and distilled through a six-inch Vigreux column. The 1-butyl-3-pyrrolidinol was collected at 138-139 degrees centigrade at 37 millimeters pressure. Yield 13.0 grams, 0.91 mole (80.5 percent).

Preparation 3.1-ethyl-3-pyrrolidinol To illustrate the use of sodium borohydride as the reducing agent for the preparation of the 3-pyrrolidinols, the 1-ethyl-3-pyrrolidone, resulting from the ring closure of 231 grams (1.0 mole) of beta-carbethoxyethylcarbethoxymethylethylamine with sodium ethoxide followed by acid hydrolysis and decarboxylation of the N-ethyl-pyrrolidone ester, was treated with a slight excess of sodium borohydride (0.28 mole) in aqueous solution near-neutrality and allowed to stand at room temperature overnight. The complex was hydrolyzed with excess 50 percent sodium hydroxide and the pyrrolidinol was extracted into chloroform. The chloroform extract was concentrated and the 1-ethyl-3-pyrrolidinol was fractionated to give 27 grams (0.235 mole, 23.5 percent) of clear white oil, 1-ethyl-3- pyrrolidinol, boiling at 117-118 degrees centigrade at 39 millimeters pressure.

The intermediate nitro compounds, the l-hydrocarbon radical substituted-3-(para-aminobenzoyloxy) pyrrolidines, are synthesized by the condensation of the appropriate 1-substituted-3-pyrrolidinol with para-nitrobenzoyl chloride in benzene or chloroform solution. In turn, the l-hyd'rocarbon radical substituted-3-(para-aminobenzoyloxy). pyrrolidines are prepared by the catalytic reduction of the corresponding l-hydrocarbon radical substituted-3- (para-nitrobenzoyloxy) pyrrolidines, as illustrated in the,

following examples.

Example 1.-I-n-butyl-3-(para-aminobenzoxloxy) pyrrolidine hydrochloride To a solution of 27.8 grams (0.15 mole) of p-nitrobenzoyl chloride in milliliters of chloroform was added 21.6 grams (0.15 mole) of 1-n-butyl-3-pyrrolidinol, in portions, and while cooling the flask in an ice bath so that the temperature did not exceed 25 degrees centigrade. The resulting solution was refluxed for three hours and concentrated at reduced pressure. The residual oil was partitioned between ether and dilute hydrochloric acid. The aqueous extract was basified with 50 percent aqueous sodium hydroxide, and the liberated base was extracted with ether. This ether extract was washed with water, dried over sodium sulfate, and acidified with ethereal hydrogen chloride, and the resulting solid was crystallized by solution in absolute ethanol and precipitation with dry ether. Yield 23.5 grams (48 percent) of l-n-butyl-3- (para-nitrobenzoyloxy) pyrrolidine hydrochloride; M. P. 167-168 degrees centigrade.

Analysis.Calculated for 01*. Found: 10.70 Ci A solution of 45 grams (0.143 mole) of l-n-butyl-3- CmHzoNzOyHCli (para-nitrobenzoyloxy) pyrrolidine hydrochloride in 400 1 milliliters of 95 percent ethanol was. shaken with five spoonfuls of Raney nickel in an atmosphere of hydrogen until the theoretical amount of gas was absorbed. The temperature of the mixture was maintained at 50-70 degrees centigrade during the reaction. The catalyst was removed by filtration, and the filtrate was concentrated at reduced pressure. The residual oil crystallized slowly from isopropyl alcohol; the solid was recrystallized from Following the procedure of this example, the l-n-hexyl 3-(para-aminobenzoyloxy) pyrrolidinehydrochloride was This compound prepared from 1-n-hexyl-3-pyrrolidinol. was a white powder having a, melt-point (M. P.) of -177 degrees centigrade. It was slightly soluble in water and soluble in alcohol. The molecular weight (M. W.) was 326.86. 7

Example 2.1-iso-butyl-3-(para-aminobenzoyloxy) pyrrolidine hydrochloride To a solution of 55.5 grams (0.3 mole) ofp-nitroben zoyl chloride in 200 milliliters of chloroform was added 43.2 grams (0.3 mole) of 1-iso-butyl-3-pyrrolidinol, in portions, and while cooling the flask in an ice bath so that the temperature did not exceed 25 degrees centigrade. The resulting solution was refluxed for three hohrs and concentrated at reduced pressure. The residual oil' was partitioned between ether and dilute hydrochloric acid. The aqueous extract was basified with 50 percent aqueous sodium hydroxide, and the liberated base was extracted with ether. This ether extract was washed with water, dried over sodium sulfate, and acidified with ethereal hydrogen chloride, and the resulting oil was crystallized from isopropyl alcohol. Yield, 65 grams (66 percent) of 1-iso-butyl-3-(para-nitrobenzoyloxy) pyrrolidine hydrochloride; M. P. -199 degrees centigrade. An analytical sample was prepared by recrystallization from absolute ethanol, M. P. 201.5-202.5 degrees centigrade.

Analysis.Calculated for C H N O .HCl: 10.78 Cl-. Found: 10.75 Cl-.

A solution of 62 grams (0.189 mole) of 1-iso-butyl-3- (para-nitrobenzoyloxy) pyrrolidine hydrochloride in 600 milliliters of absolute ethanol was shaken with five spoonfuls of Raney nickel in an atmosphere of hydrogen until the theoretical, amount of gas was absorbed. The

grams. (91 percent) of l-iso-butyl-3-(para-aminob'enzoyloxy) pyrrolidine; B. P. 147 degrees centigrade at 0.008 millimeters. On cooling the material solidified as a white powder; M. P. 68-70 degrees centigrade. 'Analysis.-CalCUlated fol C15H22N202: Found: 10.67 N. l

The product was insoluble in water as the base.

Example 3.-1-tert-butyl-3-(para-aminobenzoyloxy) pyrrolidine hydrochloride -Tov a solution of 111.0 grams (0.6 mole) of p-nitrobenzoyl chloride in 250milliliters of benzene was added 86.4' grams (0.6- mole) of 1-tert-butyl-3-pyrrolidinol, in

portions, and while cooling the flask in an ice bath so that the temperature did not exceed 25 degrees centigrade. Because of a solid which separated from solution, 200 milliliters of chloroform was added and the mixture was refluxed for three hours, cooled, filtered, and the precipitate was recrystallized from absolute alcohol. Yield 118 grams (60 percent) of 1-tert-butyl-3-(paranitrobenzoyloxy),pyrrolidine hydrochloride; M. P. 245- 247 degrees centrigrade. An analytical sample was prepared by recrystallization from absolute alcohol; M. P. 245-248 degrees centigrade.

Analysis-Calculated for C H N O HCl; 10.78 C1". Found: 10.63 Cl. I

.A suspension of 81.5 grams (0.248 mole) of l-tertbutyl-3 (para-nitrobenzoyloxy) pyrrolidine hydrochloride in 400 milliliters of 95 percent ethanol was shaken with five spoonfuls'of Raney nickel in an atmosphere of hydrogen until the theoretical amount of gas was absorbed. The temperature of the mixture was maintained at 50-70 degrees centigrade during the reaction. The catalyst was removed by filtration, and the residue was concentrated toabout 350 milliliters at reduced pressure where precipitation of the product began. The mixture was cooled inan ice bath and filtered, andthe solid was recrystallizedv from 95 percent ethanol. Yield 42 grams (58.5 percent) of 1-tert-butyl-3-(para-aminobenzoyloxy) pyrrolidine hydrochloridegM. P. 248-250 degrees centigrade.

. Analysis. Calculated for C HgzNgOg-HC1 Cl. Found: 11.68 Cl. p

The product was a white powder soluble in water.

' Example 4.-1-cyclohexy-3-(para-aminobenzoyloxy) a pyrrolidine hydrochloride To'a solution'of 93 grams (0.5 mole) of p-nitrobenzoyl chloride in 350 milliliters of chloroform was added 85 grams (0.5 mole) of 1-cyclohexy1-3-pyrrolidinol, in portions, and while cooling the flask in an ice bath so that the temperature did not exceed 25 degrees centigrade. The resulting solution was refluxed for three hours and concentrated at reduced pressure. The residual oil was partitioned between ether and dilute hydrochloric acid. The aqueous extract Was basified with 50 percent aqueou's sodium hydroxide, andthe liberated base was extracted with ether. This ether extract was washed with water, dried over sodium sulfate, and acidified with ethereal hydrogen chloride and the resulting oil wascrystallized and recrystallizedfrom an absolute ethanol-ether mixture. Yield 49 grams (27.5 percent) of l-cyclohexyl-3-(para-nitrobenzoyloxy) pyrrolidine hydrochloride; M. P. 140-150 degrees centigrade.

Anaylsis- -Calculated for C H N O HCl: 9.99 Cl. Found: 9.50 Cl. 5 1

This material was carried to the reduction step without further purification.

A solution of 49 grams (0.138 mole) of l-cyclohexyl- 3-(para-nitrobeuzoyloxy) pyrrolidine hydrochloride in 400 milliliters of absolute ethanol was shaken with five spoonfuls of Raney nickel in an atmosphere of hydrogen until the theoretical amount of gas was absorbed. The

temperature of the mixture was maintained at 50-70 degrees centigrade during the reaction. The catalyst was Example 5.1-benzyl-3-(para-aminobenzoyloxy) pyrrolidine hydrochloride To a solution of 18.6 grams (0.1 mole) of p-nitrobenzoyl chloride in 100 milliliters of benzene was added 17.7 grams (0.1 mole) of 1-benzy1-3-pyrrolidinol, in por- ;tions, while cooling the flask in an ice bath so that the temperature did not exceed 25 degrees centigrade. The resulting mixture was refluxed one hour, cooled and filtered. The solid product was crystallized from ethanol. Yield 32.5 grams (99 percent) of l-benzyl-3(para-nitrobenzoyloxy) pyrrolidine hydrochloride; M. P. 242-247 I degrees centigrade. I

Analysis.-Calculated for C H N O .HCl: 9.77 Cl'". Found: 10.02 Cl-. 7 l

A solution of 25 grams (0.08 mole) of 1-benzyl-3- (para-nitrobenzoyloxy) pyrrolidine hydrochloride in 300 40 milliliters of 95 percent ethanol was shaken with five spoonfuls of Raney nickel in an atmosphere of hydrogen until "the theoretical amount of gas had been absorbed.

- The temperature was maintained at 50-70 degrees centigrade during the reaction. The catalyst was removed by filtration; the filtrate was concentrated; and the residual oil was crystallized from isopropyl alcohol. Yield 16 grams (60 percent) of l-benzyl-3-(para-aminobenzoyloxy) pyrrolidine hydrochloride; M. P. 138-143 degrees centigrade.

Analysis-Calculated for C H N O .HC1: 10.65 Cl. Found: 10.42 CI-.

The product was a tan powder soluble in water. molecular weight (M. W.) was 332.83.

Example 6.1-phenyl-3- (para-aminobenzoyloxy pyrrolidine To a solution of 22.2 grams (0.12 mole) of p-nitrobenzoyl chloride in 250 milliliters of benzene was added 19.5 grams (0.12 mole) of l-phenyl-S-pyrrolidinol, in portions, and while cooling the flask in an ice bath so that the temperature did not exceed 25 degrees centigrade. The resulting mixture was refluxed for one hour and cooled. The benzene was decanted and the residual oil crystallized when stirred with 6 N-hydrochloric acid and proved to be the free base of the product which after several crystallizations from ethanol melted at 140.5-142 degrees centigrade. Yield 29 grams (77 per- The cent) of 1-phenyl-3-(para-nitrobenzoyloxy) pyrrolidine.

Analysis.Calculated for 8.97 .N. Found 8.77 N.

A suspension of 24 grams (0.08 mole) of 1-phenyl-3- (para-nitrobenzoyloxy) pyrrolidine in 200 milliliters of percent ethanol was shaken with five spoonfuls of Raney nickel in an atomsphere of hydrogen until the theoretical amount of gas was absorbed. The temperature of the mixture was maintained at 50-70 degrees centigrade during the reaction. The catalyst was removed by filtration and the filtrate was concentrated at reduced pressure and cooled in an ice bath which caused the precipitation of 8.5 grams (37.6 percent) of product, 1 phenyl 3 (para aminobenzoyloxy) pyrrolidine; M. P. 140-141.5 degrees centigrade.

Analysis.Calculated for C H N O Found: 10.13 N.

Example 7.1-n-0ctyl-3-(para-aminobenzoyloxy) pyrrolidine hydrochloride To a solution of 15.4 grams (0.083 mole) of p-nitrobenzoyl chloride in 75 ml. of benzene were added 15 grams (0.075 mole) of 1-n-octyl-3-pyrrolidinol, in portions, while cooling the flask in an ice bath so that the temperature did vnot exceed 25 C. The resulting mixture was refluxed one hour, cooled and filtered. The solid product was crystallized from butanone. Yield 19.5 grams (67.5 percent) of l-n-octyl-3-(para-nitrobenzoyloxy) pyrrolidine hydrochloride; M. P. 162- A suspension of 18 grams (0.0468 mole) of l-n-octyl- 3-(para-nitrobenzoyloxy) pyrrolidine hydrochloride in 100 ml. of absolute ethanol was shaken with 0.3 g. of platinum dioxide in an atmosphere of hydrogen until the theoretical amount of gas had been absorbed. The temperature was maintained at 50-70 C. during the reaction. The solution was clarified by filtration, concentrated and the residual oil was crystallized from butanone. Yield 16.5 g. (99.4 percent) of 1-n-octyl-3-(para-aminobenzoyloxy) pyrrolidine hydrochloride; M. P. 98-100 C.

Analysis.Oalculated for C H N O HCl: 9.99 Cl. Found: 10.01 Cl.

Utilizing the general procedure of the preparations and examples, the following comparative compounds were made in which the substituent attached to the N- or l-position was a hydrocarbon radical having less than four carbon atoms.

C-mizparative Example A.1-ethyl-3-(para-aminobenzoyloxy) pyrrolidine To a solution of 55.5 grams (0.3 mole) of p-ni'trobenzoyl chloride in 200 milliilters of chloroform was added 34.5 grams (0.3 mole) of 1-ethy1-3-pyrrolidinol, in portions, and whilecooling the flask in an ice bath so that the temperature did not exceed degrees centigrade. The resulting solution was refluxed for three hours and concentrated at reduced pressure. The residual oil was partitioned between ether and dilute hydrochloric acid. The aqueous extract was basified with 50 percent aqueous sodium hydroxide, and the liberated base was extracted with ether. This ether extract was washed with water, dried over sodium sulfate, filtered, and acidified with ethc ealhydrogen chloride, and the resulting oil was crystallized from absolute ethanol. Yield 48 grams (53.5 percent) of 1-ethyl-3-(para-nitrobenzoyloxy) pyrrolidine hydrochloride; M. P. 165-167 degrees centigrade. An analytical sample was prepared by recrystallization from absolute ethanol; M. P. 166.5-167 degrees centigrade.

Analysis-Calculated for C H N O .HCl: 11.79 Cl. Found: 11.70 Cl.

A solution of grams (0.15 mole) of 1-ethyl-3-(paranitrobenzoyloxy) pyrrolidine hydrochloride in 400 milliliters of absolute ethanol was shaken with five spoonfuls of Raney nickel in an atmosphere of hydrogen until the theoretical amount of gas was absorbed. The temperature of the mixture was maintained at -70 degrees centigrade during the reaction. The catalyst was removed by. filtration and the filtrate was concentrated at reduced pressure. The residual oil was dissolved in water and the organic base was precipitated by basification with 50 percent aqueous sodium hydroxide. Yield 32 grams (92 percent) of 1-ethyl-3- (para-aminobenzoyloxy) pyr- Comparative Example B.1-n-pr0pyl-3 (para-aminobenzayloxy) pyrrolidine To a solution of 55.5 grams (0.3 mole) of p-nitrobenzoyl chloride in 200 milliliters of chloroform was added 36.8 grams (0.3 mole) of 1-n-propyl-3-pyrrolidinol, in portions, and while cooling the flask in an ice bath so that the temperature did not'exceed 25 degrees centigrade. The resulting solution was refluxed for three hours and concentrated at reduced pressure. The residual oil was partitioned between ether and dilute hydrochloric acid. The aqueous extract was basified with 50 percent aqueous sodium hydroxide, and the liberated base was extracted With ether. This ether extract was washed with water, dried over sodium sulfate, and acidified with ethereal hydrogen chloride, and the resulting oil was crystallized from absolute ethanol. Yield 47 grams (50 percent) of l-n-propyl- 3 (para-nitrobenzoyloxy) pyrrolidine hydrochloride; M. P. 145-147 degrees centigrade. An analytical sample was prepared by recrystallization from absolute ethanol; M. -P. 1-45-147 degrees centigrade.

Analysis-Calculated for C H N O .HCl: 11.27 Cl. Found: 11.18 C1.

A solution of 31 grams (0.11 mole) of 1-n-propyl-3- (part-nitrobenzoyloxy) pyrrolidine hydrochloride in 400 milliliters of absolute ethanol was shaken with five spoonfuls of R-aney nickel'in an atmosphere of hydrogen until the theoretical amount of gas was absorbed. The temperature of the mixture was maintained at 50-70 degrees centigrade during thereaction. The catalyst was removed by filtration, and the filtrate was concentrated at reduced pressure. The residual oil was dissolved in water and the organic base was liberated by basification with 50 percent aqueous sodium hydroxide and extracted with ether. The etheral solution was Washed with water, dried over sodium sulfate, and concentrated, and the residue was fractionated at reduced pressure. Yield 19 grams (71 percent) of 1-n-propyl-3-(para=a-minobenzoyloxy) pyrrolidine; B. P. 157 degrees centigrade at 0.1 milliliter.

Analysis.Calculated for Found: 11.11 N.

The product was a viscous, clear pale yellow oil which was insoluble in water as the base but soluble in water containing one equivalent of acid. The molecular weight (M. W.) was 248.32.

Comparative Example C.1-allyl-3-(para-aminobenzoyloxy) pyrrolidine To a solution of 22.2 grams (9.12 moles) p-nitrobenzoyl chloride in 250' milliliters of benzene was added 15.3 grams (0.12 mole) of 1-a1lyl-3-pyrrolidinol, in portions, and while cooling the-flask in an ice bath so that the temperature did not exceed 25 degrees centigrade. The resulting mixture was refluxed for one hour and cooled. The benzene was decanted and the residue was crystallized from percent ethanol. Yield 19.2 grams (50 percent) of 1 allyl-3-(para-nitrobenzoy1oxy) pyrrolidine hydrochloride; M. P. 153-156 degrees centigrade.

Analysis.Calculated for C H N O .HCl: 11.34 Cl. Found: 11.69 Cl.

A solution of 7.8 grams (0.025 mole) of 1-allyl-3- (para-nitrobenzoyloxy) pyrrolidine hydrochloride in 150 milliliters of glacial acetic acid was treated portionwise with 20 grams (0.3 mole) of zinc dust over a period of twenty minutes and then boiled and stirred for ten minutes. The resulting near-colorless solution was filtered from the excess zinc and zinc oxide, diluted with several volumes of ice and water, basified with concentrated aqueous sodium hydroxide and extracted with ether. The ethereal extract was washed with water, dried over sodium sulfate and concentrated; and the residue was fractionated at reduced pressure. Yield 2.6 grams (42.3 percent) of 1-allyl-3-(para-aminobenzoyloxy) pyrrolidine; B. P. 195- 197 degrees centigrade at 0.5 millimeter.

Analysis-Calculated for C H N O 68.27 C; 7.36 H. Found: 68.39 C; 7.23 H.

The product was an amber oil soluble in water as the hydrochloride salt. The molecular weight (M. W.) was 246.30. The product was a silver white crystalline solid insoluble in water but soluble in alcohol, propylene glycol and dilute acids.

The toxicity as well as activity of members of this group of compounds was studied and shown by animal experiments on mice and guinea pigs, and comparison was made with known local anesthetics such as procaine and xylocaine.

The acute toxicity tests were made on groups of unstarved male albino mice by acute intraperitoneal administration and statistical calculation of the LD s was made by the method of Litchfield and Wilcoxon, 96 J. Pharm. Exptl. Therap. 99 (1949). The LD 's were expressed in mg./ kg. of body weight on the animal. Toxicity values of the preferred compounds were found to compare favorably with those of xylocaine.

Potency studies were conducted with white guinea pigs.

and comparison made with xylocaine and procaine. In this procedure, as modified for screening purposes, the backs of white guinea pigs were closely clipped and the test materials were injected intradermally into the clipped skin area. Four guinea pigs were used per dilution of the compounds. Physiological saline dilutions of 1:250, 1:500, 1:750 and 1:1000 of the candidate materials, xylocaine and procaine were prepared. 1-n-hexyl-3-(paraaminobenzoyloxy) pyrrolidine hydrochloride appeared to be insoluble at 1:250; therefore, it was excluded from the studies at this dilution. Due to unsatisfactory solubility properties, the 1-phenyl-3-(para-aminobenzoylpxy)- pyrrolidine was excluded entirely from the potency studies. A volume of 0.25 milliliter of the respective dilution of each compound and of physiologic saline was injected intradermally in parallel rows on each side of the midline, and the resulting wheals were marked for future identification. In order to neutralize any ditference in sensitiveness between frontal and caudal areas, the injection sites for any one dilution of the materials were alternated among the four pigs. The wheals were tested five minutes after injection and every five minutes thereafter, for 30 minutes. At each test, the wheals were stimulated by a series of six pin pricks. The number of pricks which failed to evoke a reflex skin twitch or phonation were counted for each test. The maximal test score for complete anesthesia, which continued for 30 minutes would be 36. The specific comparison of the potency of the compounds depended upon plotting the logarithm of the dilution against the average number of anesthetic responses (30 minute period) in each group of guinea pigs, a total of five anesthetic responses was considered the threshold anesthetic dose (TAD and furnished the basis for comparison. The TAD was read from the graph and then expressed as a ratio to the controls, xylocaine and procaine.- The results of both toxicity and potency tests for some of the preferred compounds within the scope of this invention and for the compounds of the comparative examples are shown in Table I.

isobutyl, l-tertiary-butyl and l-cyclohexyl, -3-(paraaminobenzoyloxy) pyrrolidines were observed to exert a favorable longer duration of action than xylocaine and procaine.

Various modifications may be made in the compositions of the present invention and it is to be understood that the invention is to be limited only by the scope of the appended. claims.

I claim: t p i 1. A compound selected from the group consisting of l-aliphatic-, and l-cyclo aliphatic-hydrocarbon radical substituted 3-(para-aminobenzoyloxy) pyrrolidines and acid addition salts thereof, said salts having pyrrolidine as the single basic component, wherein said aliphatic hydrocarbon radical contains at least 4 and less than 9 carbon atoms.

2. l-isobutyl-3-(para-aminobenzoy1oxy) pyrrolidine.

3. 1-tert-butyl-3-(para-aminobenzoyloxy) pyrrolidine.

4. 1-n-butyl-3-(para-aminobenzoyloxy) pyrrolidine. 5.1-cyclohexyl-3-(para-aminobenzoyloxy) pyrrolidine. 6. l-n-octyl-S-(para-aminobenzoyloxy) pyrrolidine.

References Cited in the file of this patent Richter; Richters Organic Chemistry, vol. IV (The Chemistry of the Carbon Compounds) pages 35 1947) Elsevier PublishingCompany, Inc., New York, N. Y.

Biel et al.: Journal of the American Chemical Society, vol. 77, pages 2250-6 (1955) (page 2253 relied on).

Hill et al.: J. A. C. 8., vol. 76, pages 3548-50, Feb. 1,

Mannich et al.: Berichte, vol. 61B, pages 263-8 (1928).

UNITED STATES PATENT OFFICE Certificate of Correction Patent No. 2,838,521 June 10, 1958 Carl D. Lunsford It is hereby certified that error appears in the printed specification of the above numbered gatent requiring correction and that the said Letters Patent should read as correcte below.

Column 1, lines 20 to 25, the formula should appear as shown below instead of as in the patent:

N lliydromrbon radical column 3, line 18, strike out hydrogen; column 5, line 54, Example 4, in the heading, for 1-cycZohemyread --1- cZohemyZ-; column 8, line 34, for M.P. 1145-l47 degrees centigrade read .P. 145-147 degrees centigrade-; line 38, for (partnitrobenzoyloxy) read -(para-nitrobenzoyloxy); line 49, for The etheral solution read TThe ethereal so1ution; column 9, line 31, for on the animal read of the amma Signed and sealed this 17th day of November 1959.

Attest:

KARL H. AXLINE, ROBERT C. WATSON, Attestz'ng Ofliaer. Omhmissz'oner of Patents. 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF 1-ALIPHATIC, AND 1-CYCLO ALIPHATIC-HYDROCARBON RADICAL SUBSTITUTED 3-(PARA-AMINOBENZOLOXY) PYRROLIDINES AND ACID ADDITION SALTS THEREOF, SAID SALTS HAVING PYRROLIDINE AS THE SINGLE BASIC COMPONENT, WHEREIN SAID ALIPHATIC HYDROCARBON RADICAL CONTAINS AT LEAST 4 AND LESS THAN 9 CARBON ATOMS. 